This invention relates in a general sense to topical biotherapeutic formulations, methods of manufacture of such formulations, and methods of treatment of human osteoarthritis and other inflammatory diseases. In a more particular sense, the invention relates to such formulations and methods that utilize compositions extracted from sour cherry seeds.
Osteoarthritis (OA) treatments presently rely on analgesics, which manage pain but fail to restore imbalances between catabolic and anabolic processes underlying OA pathogenesis. Previously developed biotherapeutic drugs (also known as biologics or biopharmaceuticals), which alter the activity of catabolic agents such as nitric oxide and inflammatory cytokines and allow tissue regeneration, were evaluated for efficacy in OA treatment. These studies failed to demonstrate dramatic abatement of OA symptoms by such drugs.
Osteoarthritis (OA), a degenerative age-related disease that affects the joints, is the most common human musculoskeletal disorder, and a leading cause of disability in elderly populations worldwide. OA onset is typically triggered by sustained biomechanical trauma, resulting in chondrocyte-mediated cartilage destruction.
Oxidative stress, created by this degradative process, promotes emergence of senescent osteoarthritic osteoblasts, which in turn enhance dysregulation of pro-inflammatory signaling and apoptotic depletion of functional joint cells, causing insufficient cartilage repair and aberrant remodeling of the extracellular matrix. Tissue damage is exacerbated by trauma-related dysregulation of normal maintenance of healthy joint homeostasis. This disruption promotes increasingly severe inflammation (synovitis), leading to adverse changes in joint fluid composition, breakdown of extracellular matrix material, and impairment of normal tissue repair.
The pathomechanisms of OA are facilitated by progressively elevated levels of the inflammatory cytokines TNF-α, and the interleukins (IL) IL-1β, IL-6, and IL-8, produced primarily by macrophages and T lymphocytes, systemically and in affected joint tissue. Signaling cascades downstream of these cytokines also increases expression of nitric oxide (NO) by mesenchymal cells (Volpi and Maccari 2005). Collectively, each of these factors contribute to joint capsule thickening, along with loss of cartilage, chondrocyte apoptosis, progressive articular dysfunction, and extreme chronic pain.
Several well-known features of the OA disease process that present very attractive therapeutic targets are illustrated in FIG. 1. For example, the production of inflammatory cytokines by activated CD3+T lymphocytes offers an excellent “choke point” for intervention in OA pathogenesis. This is due to critical roles for these mediators in disease-associated pain and articular tissue destruction. Many treatments interfere with inflammatory cytokines at the level of their interaction with their normal physiological receptors and block downstream signaling processes, including dysregulated inflammation. However, a class of agents known as biotherapeutic drugs is distinguished by mechanisms that modulate cellular signaling pathways to interfere with disease progression, promoting activities that contribute to healthy homeostasis. These approaches differ from use of analgesics and related drugs currently favored in clinical practice, which may ameliorate pain and other symptoms, but have a negligible effect on the fundamental pathomechanisms of OA.
Previous clinical trials of inflammatory cytokine inhibitors reported by other investigators failed to produce dramatic improvement of OA prognoses. Inhibitors of both TNF and IL-1β were constructed as fusion products of a synthetic genetic element containing a portion of the gene for cognate receptors of TNF or IL-1β, spliced to the Fc (constant) portion of the Immunoglobin G1 (IgG1) antibody. The resulting fusion protein binds to each cytokine, competitively reducing their physiological availability, thereby inhibiting their pro-inflammatory effects. In OA, this includes destruction of joint tissue (FIG. 1). These agents, administered systemically or via intra-articular injection to OA patients affected in both knees and hands, failed to halt structural deterioration or severity of symptoms. Moreover, genetically engineered cytokine inhibitors are extremely costly. For instance, per-patient costs for a one-year regimen of Etanercept, a TNF-inhibitory fusion protein with broad application in inflammatory disease, is approximately $20,000. This class of drug and related products is also associated with severe side effects, including cancer and, occasionally, fatal immune impairment.
The lack of effective biopharmaceutical strategies for OA management has left clinicians heavily dependent on corticosteroids and non-steroidal anti-inflammatories. Despite being highly effective in controlling inflammation, these drugs are often severely toxic, particularly over extended time periods. Conversely, biotherapeutic strategies avoid small molecule inhibitors of pro-inflammatory signaling cascades—which may be costly, toxic, and only marginally effective.
It is an object of this invention to provide a novel formulation or composition of matter comprising the combination of sour cherry seed extract (SCE) and sour cherry seed oil (SCO) as an inducer of heme oxygenase-1 (HO-1), a major physiological protectant against oxidative stress, in order to significantly reduce joint pain and activation of CD4+ T cells expressing inflammatory cytokines (p<0.05); to significantly decrease peripheral blood c-reactive protein (CRP); and to significantly increase leukocyte HO-1 (p<0.05). The composition inhibits joint-damaging inflammatory mediator production, thereby meeting the main criterion for classification as a biotherapeutic, i.e., an agent that inhibits disease pathogenesis rather than merely managing pain or reducing symptoms. It is a further object to provide a method of manufacture whereby the composition is formulated as a topical cream, and a further object to provide a method of treatment by topical application of the composition wherein systemic concentrations of bioactive compounds are delivered transdermally to ameliorate inflammation.